Production of beta-acylamido-beta-carbaldoxy piperidones



Patented July 4, 1950 2,513,831 ICE PRODUCT-ION F ,B-ACYLAMIDOep CAR- t BALKOXY PIPERIDONES Donald T. Warner and Owen A. Moe, Minneape olis, Minn., assignors to General Mills, Inc., a

corporation of Delaware No Drawing. Application-January25, 1947,

Serial No. 724,461

Claims. (01. 2505294) The present invention relates to a process of preparing substituted piperidones, particularly the preparation of piperidones suitable for the synthesis of ornithine.

The piperidones contemplated by the present invention include those having the following structural formula:

I /NHR S coon o N H COOR B NHCOOR in which the two R groups may be alike or different and in which R and R may be as above defined. These aldehydes may be prepared according to any of a number of methods disclosed in our copending application, Serial No. 648,020, filed February 15, 1946, and entitled Aldehydo Compounds and Processes of Producing the same.

The piperidones may be prepared from these aldehydes by converting the aldehyde to the phenylhydrazone and reducing phenylhydrazone to the piperidone in accordance with the following reactions:

0 0 OR RNHA? C O O R NHNH2 CH2 5H.

COOR NHR R NH C 0 OR C 0 OR H2 s H; Y 0 AH H H=NNH S The preparation of the phenylhydrazone from the aldehyde may be accomplished by treating the aldehyde with phenylhydrazine and glacial a 2 acetic acid. The reaction mixture is warmed for ashort. time and'then cooled. and diluted with water. to apslight turbidity. The reaction mixture is then-allowed to stand in the cold until the resultant phenylhydrazone crystallizes out and is collected by filtration. The phcnylhydrazone may be reduced to the piperidone by re: duction in the presence of Raney nickel at 701 C. and 1500-2000 pounds hydrogen pressure. After a suitable reaction time, the catalyst may be removed by filtration and the piperidone crystallized-from the reaction mixture by concentration of the alcohol solution and addition of ether The piperidone may be converted to ornithine by h dr y it c nc n ra ed yd och o c acid. T e reaction mixture is e luxed for a extended period of time and is then concentrated to a viscousv residue. From ,thisresidue ornithine monohydrochloride may be obtained as a crystalli m teri l- Th monohyd ch or e a be converted to the amino acid in accordance with known methods. The amino acid was characizs b e arin he dip s a d d b n o derivatives which melted at 197-l98", C. with de. co nssi qnandat 84 8 .C. respect v y- The following example will serve to illustrate the invention:

" "EXAMPLE A. Preparation of 'gamma,gamma+dicarbethoxyg'amma-ac'etamido butyraldehyde 10,0 partsof absolute ethyl alcohol were treated w t ar of e all so um- When h reaction of thesodium was complete, (i317. parts of ethyl acetamidomalonate were added. The resultant reaction mixture was a thick slurry, and was cooled to 3 C. in an ice bath. Then 12.9 parts ,of acrolein were introduced dropwise, After the addition of approximately 4 parts of the, acrolein, the reaction temperature had in: creased o T e odu t on of h ae olein was interrupted, and the reaction tempera ur ss assd to 8 C- Th sm nds of the acrolein was added at a rate such that the .reaction temperature was maintained at 8-10? c. Afterthe addition of the acrolein was complete, the reaction mixturewas Stirred for an additional 30-minute period. The solution was clear and lie t r wn n color- ..Du ine the a ti n of h ec s theso d initia y r sen h d d appeared. The clear, light-colored solution was cooled in an ice bath for an additional hour after which the catalyst was neutralized by the addition of 1.5 parts of lacial acetic acid dissolved in a sman amount Oi ethanol. The pH of the reactionmixture at this point was between 4-. and The resulting mixture was placed in .a refrigerator overnight. After standing overnight th sl tion was filtereda d h sol en as re accordance with known procedures.

moved by evaporation in vacuo. The residual oil was very clear and possessed a light yellow-brown 1 color. 13. Preparation amido butyraldehyde An .alcoholic solution consisting of 17.9 parts of the above aldehydo compound and approximately 100 parts of ethanol was mixed with 9.5 parts of phenylhydrazine and 1.5 parts of glacial acetic acid. The resulting reaction mixture was warmed for a few minutes on a water bath, then cooled and diluted with water to slight turbidity.

The reaction mixture was allowed to stand in the refrigerator overnight and the resulting crystalline product was collected by filtration. The

filtrate was again diluted with water to slight turbidity and, after standing overnight, the second crop of crystals was collected by filtration. The crystalline products were combined and washed with ethanol. The phenylhydrazone melted at 137138.5 C.

C. Preparation of beta-acetamz'do-b'etacarbethoxy piperidone An alcoholic suspension consisting of 15.7 parts of the phenylhydrazone of gamma-acetamidogamma,gamma-dicarbethoxy butyraldehyde and 90 parts of absolute ethanol was reduced in the presence of Raney nickel catalyst at 1760 pounds initial pressure. During the reduction the temperature was maintained at 70 C. for three hours,

and for an additional hour at 100 C. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to a syrup. Ether was added and the concentration in vacuo was repeated. The second addition of ether yielded a crystalline product which was collected by filtration, washed with ether and dried in vacuo. The beta-acetamido-beta-carbethoxy piperidonethus prepared melted at 136 to 137.5 C.

D. Preparation of ornithine 2.3 parts of beta-acetamido-beta-carbethoxy piperidone were mixed with parts of concentrated hydrochloric acid. The reaction mixture was refluxed for a period of 4.5 hours. The resulting solution was then concentrated in vacuo to a viscous residue which was dissolved in 6 parts of ethanol. The alcoholic solution was treated with 1.4 parts of concentrated ammonium hydroxide. The immediate formation of a precipitate was noted, and after chilling for one hour,

the precipitated product was collected by filtration. The collected product was suspended in absolute ethanol and the alcoholic suspension was boiled for approximately 10 minutes. The monohydrochloride of ornithine was finall collected, washed with absolute ethanol, and dried in vacuo. After purification it melted at 224- 225 C, with decomposition. The monohydrochloride may be converted to the amino acid in The diplorate of ornithine was prepared in a conventional thuric acid (dibenzoyl ornithine) was prepared and was found to melt at 184.5-185 C.

The above described process of preparing piperidones may be carried out in substantially the same manner where R and R in the previously described formula are varied as there disclosed. Likewise the aldehydes having the various R and R substituents may be prepared in essentially of thlz phenylhydrazone of gamma,gamma dicarbethozcy gamma acet- 'manner for identification purposes and was found to melt at 197-198 C. with decomposition. Orni- '4 the same manner as that described for :the preparation of gamma,gamma-dicarbethoXy-gammaacetamido butyraldehyde.

While various modifications of the invention have been described, it is to be understood that the invention is not limited thereto, but may be varied within the scope of the following claims.

We claim as our invention: 1. Process of producing piperidones having the following structural formula:

NHRI

in which R is a, low alkyl group and R is an acyl group, from aldehydes having the following formula:

coon R NHd-oooR Hi I in which R and R are as above defined, which comprises reacting the aldehyde with phenylhydrazine to form the phenylhydrazone of the aldehyde and reducing the phenylhydrazone to the piperidone.

2. Process of producing piperidones having the following structural formula:

NHR

S COOR O N H in which R and R are as above defined, which comprises reacting the aldehyde with phenylhydrazine to form the phenylhydrazone of the aldehyde, subjecting the phenylhydrazone to catalytic hydrogenation at a pressure within the approximate range of 1500-2000 pounds, and at a temperature of 70-l20 C. to produce the piperidone.

3. Process of producing piperidones having the following structural formula:

NHR

COOR

R NH

in which R is a low alkyl group and R is a sulfonyl group, from aldehydes having the following formula:

000R n Nm zcooa in which R and R are as above defined, which comprises reacting the aldehyde with phenylhydrazine to form the phenylhydrazone of the aldehyde, subjecting the phenylhydrazone t0 catalytic hydrogenation at a pressure within the approximate range of 1500-2000 pounds, and at a temperature of Til-120 C. to produce the piperidone.

4. Process of producing piperidones having the following structural formula:

which. comprises reacting the aldehyde with phenylhydrazine to form the phenylhydrazone of the aldehyde and reducing the phenylhydrazone to the piperidone.

5. Process of producing piperidones having the following structural formula:

NHCOCH;

s OOOEt O N H from aldehydes having the following formula:

0 0 0 Et onto ONH(IJO o 0 Et which comprises reacting the aldehyde with phenylhydrazine to form the phenylhydrazone of the aldehyde, subjecting the phenylhydrazone to catalytic hydrogenation at a pressure within the approximate range of 1500-2000 pounds, and at a temperature of -120 C. to produce the piperidone.

DONALD T. WARNER.

OWEN A. MOE.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Bergel et al Aug. 13, 1946 OTHER REFERENCES Fischer: Berichte 42, pp. 4878-4886 (1909).

Bergmann et al., Zeit fur Physiol Chem., vol. 159 (1926), pp. 179-189.

Sidgwick, Organic Chemistry of Nitrogen (1942), pp. 16, 17, 393, 394, 395.

Albertson, J. Amer. Chem. Soc., vol. 67, pp. 2043, 2044 (1945).

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1. PROCESS OF PRODUCING PIPERIDONES HAVING THE FOLOWING STRUCTURAL FORMULA: 